Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Urokinase-type plasminogen activator (uPA) and its specific membrane receptor (uPAR) control extracellular matrix proteolysis, cell migration, invasion and cell growth in several cancers. The uPAR released from human cancers is detected in blood as soluble uPAR (suPAR). No information is available on the mechanism(s) of action of suPAR on prostate cancer (PCa) cell growth and invasion. In order to clarify this issue, we tested the effect of a treatment with the human recombinant suPAR (comprising amino acids l-303) on the proliferation, migration and invasion of DU145 cells, a PCa cell line expressing a potent autocrine uPA-uPAR signalling system. The results indicate that suPAR significantly inhibits cell growth, promotes apoptosis and decreases both migration and Matrigel invasion of DU145 cells. The mechanism of action of suPAR seems to be linked to a decrease of ERK and FAK activation. Cleavage of suPAR by chymotripsin reverses these effects. When added to the uPA-negative LNCaP cells, suPAR was ineffective; on the contrary, when LNCaP cells were cultured on fibronectin-coated plates in order to stimulate uPA expression, suPAR significantly decreased cell proliferation. In conclusion, our data suggest that suPAR can function as a potent molecule scavenger for uPA in human PCa cells characterized by high levels of uPA/uPAR as in DU145 cells, while it is ineffective in uPA-deficient LNCaP cells. The molecular mechanism(s) through which suPAR participates in the control of PCa progression may bear relevance for the long-term goal to identify new therapeutic targets aimed at silencing tumours in vivo.
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PMID:suPAR, a soluble form of urokinase plasminogen activator receptor, inhibits human prostate cancer cell growth and invasion. 1809 58

Endocytic pathways have been implicated in polyamine transport in mammalian cells, but specific mechanisms have not been described. We have shown that expression of a dominant negative (DN) form of the GTPase Dynamin, but not Eps15, diminished polyamine uptake in colon cancer cells indicating a caveolar and nonclathrin uptake mode. Polyamines co-sediment with lipid raft/caveolin-1 rich fractions, of the plasma membrane in a sucrose density gradient. Knock down of caveolin-1 significantly increased polyamine uptake. Conversely, ectopic expression of this protein resulted in diminished polyamine uptake. We also found that presence of an activated K-RAS oncogene significantly increased polyamine uptake by colon cancer cells. This effect is through an increase in caveolin-1 phosphorylation at tyrosine residue 14. Caveolin-1 is a negative regulator of caveolar endocytosis and phosphorylation in a K-RAS dependent manner leads to an increase in caveolar endocytosis. In cells expressing wild type K-RAS, addition of exogenous uPA was sufficient to stimulate caveolar endocytosis of polyamines. This effect was abrogated by the addition of a SRC kinase inhibitor. These data indicate that polyamine transport follows a dynamin-dependent and clathrin-independent endocytic uptake route, and this route is positively regulated by the oncogenic expression of K-RAS in a caveolin-1 dependent manner.
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PMID:Activated K-RAS increases polyamine uptake in human colon cancer cells through modulation of caveolar endocytosis. 1817 34

The scavenger receptor low-density lipoprotein receptor-related protein 1 (LRP-1) mediates the clearance of a variety of biological molecules from the pericellular environment, including proteinases which degrade the extracellular matrix in cancer progression. However, its accurate functions remain poorly explored and highly controversial. Here we show that LRP-1 silencing by RNA interference results in a drastic inhibition of cell invasion despite a strong stimulation of pericellular matrix metalloproteinase 2 and urokinase-type plasminogen activator proteolytic activities. Cell migration in both two and three dimensions is decreased by LRP-1 silencing. LRP-1-silenced carcinoma cells, which are characterized by major cytoskeleton rearrangements, display atypical overspread morphology with a lack of membrane extensions. LRP-1 silencing accelerates cell attachment, inhibits cell-substrate deadhesion, and induces the accumulation, at the cell periphery, of abundant talin-containing focal adhesion complexes deprived of FAK and paxillin. We conclude that in addition to its role in ligand binding and endocytosis, LRP-1 regulates cytoskeletal organization and adhesive complex turnover in malignant cells by modulating the focal complex composition, thereby promoting invasion.
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PMID:LRP-1 silencing prevents malignant cell invasion despite increased pericellular proteolytic activities. 1831 5

Osteosarcoma (OS) is a cancer which afflicts the bone, ending in usually fatal lung metastasis mainly in teenagers and adolescents. We have recently shown that PEDF is one biological that has multiple anti-OS activity. In parallel, we have also shown using rodent cells, the beneficial effects of downregulation of uPAR against OS. Here, we provide further proof of such effects of uPAR downregulation using human OS cells and combine this with PEDF treatment. We describe the involvement of uPAR with activity of PEDF. In silico, PEDF did not bind to uPA and thus did not attenuate its activity. In the presence of exogenous PEDF, both uPA, its receptor and FAK localize intracellularly. Blocking of uPA and uPAR on the cell surface increased the binding of PEDF, whether endogenous or exogenous. In clinical specimens of OS, there was mutually exclusive expression of PEDF and uPAR at the growing edge of the tumor. Incubation of cells with PEDF and a uPAR antibody led to an increased reduction in invasion of cells through Matrigel, and a heightened apoptotic signal. In vivo, treatment of human OS cells with both PEDF and uPAR DNAzyme resulted in greater primary tumor growth, pulmonary metastasis inhibition and decreased osteolysis. Areas of necrosis were noted in the PEDF-administered group of animals. This study shows an association between two very important systems involved in tumor progression and highlights the possibility that a combined approach of PEDF exposure and uPAR knockdown may lead to a better targeted outcome against OS.
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PMID:uPAR mediates anticancer activity of PEDF. 1848 55

We have previously reported that Bcl-w enhances the invasiveness of gastric cancer cells by inducing MMP-2 expression via phosphoinositide 3-kinase (PI3K), Akt and Sp1. This study demonstrates that Bcl-w additionally induces uPA expression and FAK activation. Analyses of the hierarchical relationship and functions of these components showed that the PI3K-Akt-Sp1 pathway also mediates the induction of uPA, and that both uPA and MMP-2 contribute to Bcl-w-induced invasion via the stimulation of the FAK-dependent migratory pathway. These findings significantly advance our understandings of the Bcl-w-induced signaling processes that results in the migration and invasion of cancer cells.
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PMID:Signaling components involved in Bcl-w-induced migration of gastric cancer cells. 1909 87

There is increasing evidence that urokinase-type plasminogen activator (u-PA) and matrix metalloproteinases (MMPs) play an important role in cancer metastasis and angiogenesis. Inhibition of u-PA and MMPs could suppress migration and invasion of cancer cells. Berberine, one of the main constituents of the plant Rhizoma coptidis, is a type of isoquinoline alkaloid, reported to have anti-cancer effects in different human cancer cell lines. There is however, no available information on effects of berberine on migration and invasion of human tongue cancer cells. Here, we report that berberine inhibited migration and invasion of human SCC-4 tongue squamous carcinoma cells. This action was mediated by the p-JNK, p-ERK, p-p38, IkappaK and NF-kappaB signaling pathways resulting in inhibition of MMP-2 and -9 in human SCC-4 tongue squamous carcinoma cells. Our Western blowing analysis also showed that berberine inhibited the levels of urokinase-plasminogen activator (u-PA). These results suggest that berberine down-regulates u-PA, MMP-2 and -9 expressions in SCC-4 cells through the FAK, IKK and NF-kappaB mediated pathways and a novel function of berberine is to inhibit the invasive capacity of malignant cells.
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PMID:Berberine suppresses in vitro migration and invasion of human SCC-4 tongue squamous cancer cells through the inhibitions of FAK, IKK, NF-kappaB, u-PA and MMP-2 and -9. 1925 61

The serine-protease urokinase (uPA) and its specific membrane receptor uPAR controls matrix degradation through the conversion of plasminogen into plasmin and play a crucial role in a number of biological processes including local fibrinolysis, inflammation, angiogenesis, matrix remodelling during wound healing, tumor invasion and metastasis. Most of the cellular responses modulated by the uPA/uPAR system, including migration, cellular adhesion, differentiation, proliferation and apoptosis require transmembrane signaling, which is mediated by direct contacts of uPAR with a variety of extracellular proteins and membrane receptors, such as integrins, EGF receptor, high molecular weight kininogen, caveolin and the G-protein-coupled receptor FPRL1. As a result of these interactions, uPAR activates intracellular signalling molecules such as tyrosine- and serine-protein kinases, Src, focal adhesion kinase (FAK), Rac, extracellular-signal-regulated kinase (ERK)/mitogen- activated protein kinase (MAPK) and JAK/STAT, being part of a large "signalosome" interacting with several molecules on both the outside and inside of the cell. This review is focused on the biochemistry of the pathways affected by uPAR and its partners.
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PMID:The urokinase receptor as an entertainer of signal transduction. 1927 72

The applicability of LC-MS/MS in precursor ion scan mode for the detection of urinary stanozolol metabolites has been studied. The product ion at m/z 81 has been selected as specific for stanozolol metabolites without a modification in A- or N-rings and the product ions at m/z 97 and 145 for the metabolites hydroxylated in the N-ring and 4-hydroxy-stanozolol metabolites, respectively. Under these conditions, the parent drug and up to 15 metabolites were found in a positive doping test sample. The study of a sample from a chimeric uPA-SCID mouse collected after the administration of stanozolol revealed the presence of 4 additional metabolites. The information obtained from the product ion spectra was used to develop a SRM method for the detection of 19 compounds. This SRM method was applied to several doping positive samples. All the metabolites were detected in both the uPA-SCID mouse sample and positive human samples and were not detected in none of the blank samples tested; confirming the metabolic nature of all the detected compounds. In addition, the application of the SRM method to a single human excretion study revealed that one of the metabolites (4xi,16xi-dihydroxy-stanozolol) could be detected in negative ionization mode for a longer period than those commonly used in the screening for stanozolol misuse (3'-hydroxy-stanozolol, 16beta-hydroxy-stanozolol and 4beta-hydroxy-stanozolol) in doping analysis. The application of the developed approach to several positive doping samples confirmed the usefulness of this metabolite for the screening of stanozolol misuse. Finally, a tentative structure for each detected metabolite has been proposed based on the product ion spectra measured with accurate masses using UPLC-QTOF MS.
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PMID:Detection and structural investigation of metabolites of stanozolol in human urine by liquid chromatography tandem mass spectrometry. 1946 4

In this study, we investigated the effect of danthron on the cell migration and invasion of human brain glioblastoma multiforme GBM 8401 cells in vitro. The changes of migration and invasion of GBM 8401 cells after treatment with danthron were detected by cell migration assay and cell invasion assay. The levels of mRNA gene expression associated with cell migration and invasion were detected by real-time PCR. Results indicated that human brain glioblastoma multiforme GBM 8401 cells treated with danthron in vitro migrated and invaded less than cells treated with phosphate-buffered saline (PBS) (control). Western blotting showed that danthron inhibited the protein levels of FAK, MMP-7, MMP-9 and uPA in GBM 8401 cells. Real-time PCR assay also showed that danthron inhibited the mRNA expression of matrix metalloproteinase-9 (MMP-9), FAK and ROCK-1 of GBM 8401 cells. These results showed that danthron inhibited invasion and migration of GBM 8401 cells by downregulating mRNA expression associated with these processes, resulting in reduced metastasis. Thus, danthron may be considered a therapeutic agent that can inhibit primary tumor growth and prevent metastasis.
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PMID:Danthron inhibits the migration and invasion of human brain glioblastoma multiforme cells through the inhibition of mRNA expression of focal adhesion kinase, Rho kinases-1 and metalloproteinase-9. 1978 17

Benzyl isothiocyanate (BITC), a component of dietary cruciferous vegetables, has antioxidant and anticancer properties. In this study, we show for the first time the antimetastatic effects of BITC in human colon cancer HT29 cells. BITC had an inhibitory effect on cell migration and invasion. Protein levels of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and urokinase-plasminogen activator (u-PA) were reduced by BITC in a concentration-dependent manner. BITC also exerted an inhibitory effect on phosphorylation of c-Jun N-terminal kinase 1 and 2 (JNK1/2), extracellular signal-regulated kinases 1 and 2 (ERK1/2), phosphatidylinositol 3-kinase (PI3K) and protein kinase C (PKC) that are upstream of nuclear factor kappa B (NF-kappaB). BITC inhibited DNA binding activity of NF-kappaB. Moreover, BITC decreased the levels of c-Fos, c-Jun, Ras, FAK, PI3K and GRB2 in HT29 cells. Reductions in the enzyme activity, protein and mRNA (mRNA) levels of MMP-2 were observed in BITC-treated HT29 cells. BITC also inhibited mRNA levels of MMP-2, -7, and -9 in HT29 cells. Results from zymography showed that BITC treatment decreased MMP-2 expression in a concentration-dependent manner. BITC inhibited PKCdelta activity in HT29 cells. Furthermore, inhibitors specific for JNK (SP600125) reduced expression of MMP-2, MMP-9, and u-PA. These results demonstrated that BITC could alter HT29 cell metastasis by reduction of MMP-2, MMP-9, and u-PA expression through the suppression of a PKC, MAPK signaling pathway and inhibition of NF-kappaB levels. These findings suggest that BITC has potential as an antimetastatic agent.
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PMID:Benzyl isothiocyanate (BITC) inhibits migration and invasion of human colon cancer HT29 cells by inhibiting matrix metalloproteinase-2/-9 and urokinase plasminogen (uPA) through PKC and MAPK signaling pathway. 2013 87


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